Trauma to the brain or spinal cord caused by physical forces acting on the skull or spinal column, by ischemic stroke, arrested breathing, cardiac arrest, Reye's syndrome, cerebral thrombosis, cerebral embolism, the neurological problems caused by AIDS, cerebral hemorrhage, encephalomyelitis, hydrocephalus, post-operative brain injury, cerebral infections, various concussions, and elevated intracranial pressure results in edema and swelling of the affected tissues. This is followed by ischemia, hypoxia, necrosis, temporary or permanent brain or spinal cord injury and may result in death. The tissues mainly affected are classified as grey matter, more specifically astroglial cells. The specific therapy currently used for treatment of medical problems described include various kinds of diuretics (particularly osmotic diuretics), steroids (such as, 6-.alpha.-methylprednisolone succinate), and barbiturates. The usefulness of these agents is questionable and they are associated with a variety of untoward complications and side effects. See, e.g., E. J. Cragoe, Jr., Medicinal Research Reviews, 1,271-305 (1987). Thus, the compounds of this invention comprise a novel and specific treatment of medical problems where no specific therapy is available.
Certain (indanyloxy)alkanoic acid derivatives have been disclosed as useful agents for the treatment and prevention of injury to the brain and spinal cord. See Cragoe et al., J. Med. Chem., 25, 567-579 (1982) and U.S. Pat. Nos. 4,579,869, 4,465,850, 4,463,208, 4,394,385, and 4,389,417. None of these publications, however, discloses the amidinoalkoxy and amidinoalkylamino indanones or salts of the present invention nor suggests their utility for treatment of brain injury or edema. Moreover, the '385 patent discloses indeno[5,4-b]furancarboxylic acids that have a structurally distinct ring system from the compounds of the present invention.
Certain [(tetrahydrofluoren-7-yl)oxy]alkanoic acid derivatives have also been disclosed as useful agents for the treatment and prevention of injury to the brain and spinal cord. See Cragoe et al., J. Med. Chem., 29, 825-841 (1986) and U.S. Pat. Nos. 4,604,396, 4,356,314, 4,356,313, 4,337,354, 4,317,922, and 4,316,043. The compounds disclosed in these publications, however, are carboxylic acid derivatives having a fluorenyl ring nucleus and thus are structurally distinct from the amidinoalkoxy and amidinoalkylamino indanones and salts of the present invention.
The compounds of the invention have the added advantage of being devoid of the pharmacodynamic, toxic or various side effects characteristic of the diuretics, steroids and barbiturates.